Evolution of Antibiotic Resistance in Enteric Bacteria

描述（由申请人提供）：细菌抗生素耐药性的发展和传播已经成为一个主要的公共卫生问题。曾经很容易被抗菌药物控制的致病菌，现在往往对大多数抗生素没有反应。大多数关于抗生素耐药性的原因和后果的研究集中在临床分离的致病菌上，即从医院感染的人身上分离出来的细菌。这些研究揭示了耐药机制和基因的多样性，耐药性如何在细菌谱系之间传播的遗传细节，并提供了这种传播在医院环境中发生的速度的估计。这种基于临床的研究在追踪抗生素耐药性演变过程的努力中起着至关重要的作用，并建议对特定病原体优先使用药物。然而，这些研究有两个关键性的遗漏。首先，临床分离的R基因只占现有R基因多样性的一小部分。现在很清楚，抗生素耐药性早于人类介导的抗生素使用，同样清楚的是，对于人类发现、设计或开发的每一种药物，几乎可以肯定的是，微生物已经拥有了一种防御机制，这种机制转移到人类病原体身上只是时间问题。如果我们要成功地规划抗微生物策略，对现有耐药机制的多样性有一个更全面的了解是至关重要的。其次，这些研究忽略了细菌及其耐药基因在自然界中所经历的复杂的生态和进化压力（除了人类介导的抗生素使用所产生的压力）。这些信息对于开发合理的治疗方法至关重要。本研究的目的是探索和对比天然和临床肠道细菌群体抗生素耐药性的演变，并将这些数据应用于开发更有效的抗生素治疗。我们在此建议对细菌自然种群的抗生素耐药性进化进行首次“全面”调查。使我们的研究更加全面的是我们对抗生素耐药性表型、基因型、遗传变异和分化水平的综合关注，对耐药性相关适应度效应的估计，以及利用这些数据为现有的抗生素治疗提供信息，并有助于设计更合理或更新颖的治疗方法。

DESCRIPTION (provided by applicant): The development and spread of bacterial antibiotic resistance has emerged as a major public health concern. Pathogenic bacteria once easily controlled by antimicrobial drugs now frequently fail to respond to most antibiotics. Most research on the causes and consequences of antibiotic resistance focuses on clinical isolates of pathogenic bacteria, i.e. isolates from infected humans in hospitals. These studies reveal the diversity of resistance mechanisms and genes, the genetic details of how resistance spreads between bacterial lineages and provide estimates of the speed with which such spread occurs in hospital settings. Such clinically based studies play an essential role in efforts to track the course of antibiotic resistance evolution and suggest the priority of drug use for particular pathogens. However, these studies suffer from two critical omissions. First, R genes characterized from clinical isolates represent a small fraction of the existing diversity of R genes. It is now clear that antibiotic resistance predates the human mediated use of antibiotics and it is equally clear that for every drug humans discover, design or develop, it is almost certainly the case that microbes already possess a defensive mechanism and it is only a matter of time before that mechanism is transferred to a human pathogen. It is critical to have a more complete understanding of the diversity of existing resistance mechanisms if we are to successfully plan antimicrobial strategies. Second, these studies ignore the complex ecological and evolutionary pressures that bacteria and their resistance genes experience in nature (in addition to those resulting from human-mediated antibiotic use). This information is critical to the development of rational treatment therapies. The goal of this research is to explore and contrast the evolution of antibiotic resistance in natural and clinical populations of enteric bacteria and to apply these data to efforts aimed at the development of more effective antibiotic therapies. We propose here the first "comprehensive" survey of antibiotic resistance evolution in natural populations of bacteria. What makes our study comprehensive is the combined focus on antibiotic resistance phenotypes, genotypes, levels of genetic variation and divergence, estimates of resistance-associated fitness effects and the use of these data to inform existing antibiotic therapies and contribute to the design of more rational or novel therapies.